Diabetes is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Diabetes is the leading cause of blindness in people ages 20 to 70 and is sixth leading cause of death in the United States. Overall, the risk for death among people with diabetes is about 2 times that of people without diabetes. The disease often leads to other complications such as kidney, nerve and heart disease and strokes. It is the leading cause for non-traumatic amputations and kidney failure.
Diabetes is reaching epidemic proportions in the United States. There are approximately 18.2 million people in the United States, or 6.3% of the population, who have diabetes. While an estimated 13 million have been diagnosed with diabetes, 5.2 million people (or nearly one-third) are unaware that they have the disease. Furthermore, diabetes is one of the most common chronic diseases in children and adolescents; about 151,000 people below the age of 20 years have diabetes.
Diabetics must diligently monitor the glucose level in their blood. Blood glucose levels should be maintained between 80 to 120 mg/dl before meals and between 100-140 mg/dl at bedtime. Self-monitoring of blood glucose (SMBG) permits diabetics to know what their blood sugar level is so they can adjust their food, insulin, or activity level accordingly. Improved glucose control can forestall, reduce, or even reverse some of the long-term complications of diabetes.
The gold standard for testing blood glucose is the measurement of glucose in a plasma sample obtained from a vein. A drop of blood is placed on a small window in a test strip. Blood glucose acts as a reagent in a chemical reaction that produces a color change or generates electrons. The color change is detected by a reflectance-meter and reported as a glucose value. Alternatively, the electrons generated in the reaction are detected as an electrical current and reported as a glucose value.
Problems with existing SMBG devices include the requirement of a drop of blood for each test (normally acquired through a prick of the finger). The blood sampling can be painful and cause calluses to form. It also increases the risk for warts and infections. The acute discomfort associated with this presents the largest barrier to life-saving blood glucose control.
Minimally invasive technologies currently on the market in the United States include the GlucoWatch® Biographer (Cygnus Therapeutic Systems Corporation, Redwood City, Calif.) and the Guardian® Continuous Glucose Monitoring System (Medtronic MiniMed, Inc., Northridge, Calif.). The GlucoWatch® Biographer uses reverse iontophoresis, which involves applying an electrical microcurrent to the skin. The current pulls sodium through the intact skin, water follows sodium and water pulls glucose with it. The glucose concentration in this fluid is proportionate to the concentration in blood.
However, there are several problems with this technology. There is a lag time of 20 minutes before a blood glucose value can be reported. The concentration of glucose in the fluid is only 1/1,000 of glucose in the blood. A mild skin discomfort last for a few minutes when the device is first applied to the skin. The device is intended for use only by adults (age 18 and older) with diabetes. It is intended to supplement, not replace, standard home blood glucose monitoring devices. The user also has to calibrate the GlucoWatch® Biographer with a blood glucose value measured on a traditional, i.e. “fingerstick,” monitor. Thus a standard (invasive) blood glucose monitor is still required.
The Guardian® Continuous Glucose Monitoring System is designed to automatically and frequently monitor glucose values in subcutaneous interstitial fluid (ISF). It measures ISF glucose every five minutes and it has a hypoglycemia alert. Once inserted, the sensor is virtually painless, but it requires entry of glucose readings from a standard monitor at least twice a day in order to calibrate the sensor. Furthermore, the readings from this monitor lag the actual blood glucose values by 15-20 minutes potentially resulting in over or under dosing of insulin.
Dexcom and Medtronic, among others, market a subcutaneously inserted continuous glucose monitor (CGM), which functions for several clays before requiring replacement. These devices, though, measure interstitial blood glucose, which frequently lags blood glucose by 15 minutes or more. This lag alone is suboptimal (more manageable lag times are in the 5-10 minute range) and lag times may tend to be inconsistent. This means that there is no one control algorithm that can be used to create a closed-loop system since the inter- and intra-sensor variability in lag is too great (5-30 minutes according to recent reports) and doesn't apply to each sensor the same way or even apply to the same sensor during certain physiological situations. For the inter-sensor variability, a sensor is placed at least weekly in the subcutaneous space. During this weekly placement, one sensor may be tightly nestled in a capillary bed (lag time 5-10 min) while the sensor implanted a week later may instead be up against a muscle fiber or a region of fat (30 minute or greater tag time). Therefore a consistent control algorithm for both sensor placements without very poor control is difficult to use.
With respect to intra-sensor variability, there are many conditions that affect blood flow to the submucosa of the skin. Cold temperature, for example, will drastically impact blood flow to the skin. Another potential impact on blood flow is sleeping. There may be significant intra-sensor variability between sleeping and waking lag periods that may have resulted in the episodes of severe nocturnal hypoglycemia with closed loop control noted in the literature.
For the foregoing reasons, there is a need for continuous analyte monitoring systems and implantable drug delivery systems that allow continuous monitoring of glucose levels accurately, for extended periods of time, and with significantly reduced lag times.